This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Natural Killer T (NKT) lymphocytes are a unique subset of T lymphocytes that have an invariant TCR Valpha chain and recognize ligands presented by the nonpolymorphic CD1d molecule. Functionally, CD1d-reactive NKT cells can secrete large amounts of both Th-1 and Th-2 type cytokines, including IL-10, and are early effectors of the innate immune system. By virtue of the diverse cytokines that they secrete, NKT cells may play a role in modulating immune activation in HIV and SIV infection. Sooty mangabeys are a natural host of SIV that do not progress to AIDS. A key differentiating feature of SIV infection in its natural host is the absence of aberrant immune activation. In this project we are investigating whether NKT cells are responsible for the lack of aberrant immune activation in naturally SIV-infected sooty mangabeys. In a cross-sectional analysis of 50 SIV-negative and 50 SIV-infected sooty mangabeys, flow cytometric evaluation of eripheral blood has revealed detectable frequencies of circulating Valpha24positive CDld-tetramer positive NKT lymphocytes in roughly 50% of sooty mangabeys. Functionally, mangabey NKT cells secrete IFN-gamma, IL-2, IL-4, IL-10, and IL-13 in a CD1d-restricted manner, and are also capable of degranulation suggesting both immunoregulatory and cytolytic functions. They also do not appear to be depleted in SIV-infected sooty mangabeys. Comparison of NKT lymphocytes in natural and non-natural hosts of SIV infection is in progress.